Every time a cell divides, it must copy three billion DNA letters without error—and a protein called SET1A helps fix the damage that inevitably occurs during this process. When SET1A is missing, cells cannot properly repair DNA breaks that happen during replication. These unrepaired breaks accumulate, leading to genetic rearrangements that can turn healthy cells into tumour cells. The problem is that scientists do not yet understand how protein methylation—the chemical modification SET1A adds to other proteins—controls this repair process, or whether faults in methylation contribute to human disease. This project will investigate three specific unknowns: how SET1A methylates a protein called BLM to enable DNA repair; whether cancer-linked mutations in a partner protein called BOD1L disrupt its ability to bind SET1A; and whether mice lacking one copy of SET1A develop blood disorders that resemble human leukaemia. This is fundamental science. It will not produce a drug or a diagnostic test in the near term. But understanding how cells protect their genome during replication has historically revealed the mechanisms behind many cancers and inherited diseases, and could eventually point toward treatments that restore proper DNA repair in patients.
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The accurate and timely duplication of the cellular genome is critical for the continuation of viable life, and this must occur efficiently to ensure that each daughter cell receives a full complement of genetic material after cell division. If the DNA to be duplicated is damaged, and this is left unrepaired, this will hinder genome replication by slowing/stalling the DNA replication machinery. Ultimately, such damage leads to genomic rearrangements that can be passed on to daughter cells, or may even result in cell death. The gradual accumulation of genetic damage over time is a fundamental factor in the transformation of healthy cells into tumour cells. Therefore, it is clear that repair of DNA damage occurring during DNA replication helps to maintain human health and prevent diseases such as cancer. To counter the effects of genetic damage during DNA replication, cells have evolved complex networks of proteins which allow the recognition and repair of damaged DNA. These proteins are regulated by an intricate series of modifications, which function to regulate their abilities to appropriately detect/repair damaged DNA. Addition or removal of these modifications is achieved by catalytic proteins known as enzymes. One such modification is methylation, which modifies the structure of several proteins, and is carried out by a specific set of enzymes. In this context, I have identified that one such methylation enzyme (called SET1A) functions to help repair damaged DNA that arises during replication. When SET1A is lost, cells are unable to properly repair such DNA damage, and these cells accumulate high levels of DNA alterations. SET1A also interacts with a protein called BLM, which functions during DNA replication and is mutated in a rare human disease (Bloom's syndrome). Early experiments suggest that SET1A methylates BLM, which may explain why loss of SET1A renders cells unable to properly repair DNA damage occurring during DNA replication. Inherited mutations in many components involved in DNA repair during replication also predispose individuals to a greater risk of developing blood disorders, ultimately leading to leukaemia. I have also shown that SET1A binds to, and acts alongside, a DNA damage protein called BOD1L. Interestingly, loss of this methylation complex (BOD1L and/or SET1A) may also be linked to the development of similar blood disorders. Together with my other data, this suggests that SET1A is crucial for controlling the response to DNA damage and preventing human disease, perhaps including leukaemia. Whilst we know that DNA repair during replication is important to maintain the cellular genome, it is unknown how protein methylation is involved in this response, or whether problems with methylation contribute to human disease. This proposal aims to investigate these further, using three complementary approaches. Firstly, I aim to establish how BLM methylation helps to promote DNA repair, and to identify other DNA repair proteins that are methylated by SET1A. Secondly, I aim to ascertain how cancer-associated mutations affect the ability of BOD1L to bind to SET1A, and whether this affects their function. Thirdly, using a mouse model, I aim to determine whether loss of one copy of SET1A affects how cells repair DNA, and whether these mice develop blood disorders. The proposed scheme of research will further our understanding of this fundamental aspect of the DNA damage response. It has the potential to make a significant impact on improving human health and wellbeing in the long term, and will lay the groundwork for future pharmacological treatments for use in treating cancers.
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